The understanding of olfactory transduction, the process used by olfactory neurons to recognize and assess the concentration of volatile odorant molecules is the ultimate goal of this project. It is clear that for a substantial number of odorants olfactory transduction takes place through receptor-mediated activation of G-proteins leading to formation of the second messenger adenosine- 3', 5'-monophosphate (cAMP). The subsequent elevation in intracilliary cAMP concentration causes opening of cAMP-gated cation channels, influx of Ca/2+ and subsequent gating of Ca/2+-activated chloride channels that depolarize olfactory receptor neurons. Furthermore, there is also controversial evidence indicating that some odors may stimulate formation of inositol-1,4,5-triphosphate electing opening of InsP/3-gated non-specific cation channels which would also elicit cell depolarization. However, in invertebrates, amphibians and fish there is solid evidence for inhibitory pathways that elicit opening of K+ channels thereby causing cell hyperpolarization, and a decrease in the frequency of action potential firing. In this grant proposal we present preliminary evidence suggesting that odorants elicits inhibitory responses in mouse olfactory receptor neurons, and we propose to study the molecular mechanisms mediating inhibitory olfactory responses in mammals, including humans, using a multidisciplinary approach including biophysical and electrophysiological measurements. In addition, we propose to determine mechanism that mediates odor-induced decreases in intracellular calcium ([Ca/2+]/i) detected in a large fraction of human olfactory neurons, that cannot be explained within the context of the currently proposed models of olfactory transduction. These studies will lead to a better understanding of olfactory transduction in mammals, including humans. These results provide the basis for studies of the cellular and molecular etiology of olfactory dysfunction in humans.